Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Casilla (P. O. Box) 567, Valdivia, Chile.
Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
Neurochem Res. 2023 Jul;48(7):2093-2103. doi: 10.1007/s11064-023-03889-w. Epub 2023 Feb 15.
Huntington's disease (HD) is a disease characterized by the progressive degeneration of nerve cells in the brain. DNA damage has been implicated in many neurological disorders; however, the association between this damage and the impaired signaling related to neurodegeneration is still unclear. The transcription factor c-AMP-responsive element binding protein (CREB) has a relevant role in the neuronal plasticity process regulating the expression of several genes, including brain-derived neurotrophic factor (BDNF). Here we analyzed the direct link between DNA damage and the expression of genes involved in neuronal plasticity. The study was performed in model cell lines STHdhQ7 (wild type) and STHdhQ111 (HD model). Treatment with Etoposide (Eto) was used to induce double-strand breaks (DSBs) to evaluate the DNA damage response (DDR) and the expression of synaptic plasticity genes. Eto treatment induced phosphorylation of ATM (p-ATM) and H2AX (γH2AX), markers of DDR, in both cell lines. Interestingly, upon DNA damage, STHdhQ7 cells showed increased expression of activity-regulated cytoskeleton associated protein (Arc) and BDNF when compared to the HD cell line model. Additionally, Eto induced CREB activation with a differential localization of its co-activators in the cell types analyzed. These results suggest that DSBs impact differentially the gene expression patterns of plasticity genes in the normal cell line versus the HD model. This effect is mediated by the impaired localization of CREB-binding protein (CBP) and histone acetylation in the HD model. Our results highlight the role of epigenetics and DNA repair on HD and therefore we suggest that future studies should explore in depth the epigenetic landscape on neuronal pathologies with the goal to further understand molecular mechanisms and pinpoint therapeutic targets.
亨廷顿病（HD）是一种以大脑神经细胞进行性退化为特征的疾病。DNA 损伤与许多神经退行性疾病有关；然而，这种损伤与与神经退行性相关的信号转导受损之间的联系仍不清楚。转录因子 c-AMP 反应元件结合蛋白（CREB）在调节包括脑源性神经营养因子（BDNF）在内的多种基因表达的神经元可塑性过程中具有重要作用。在这里，我们分析了 DNA 损伤与参与神经元可塑性的基因表达之间的直接联系。该研究在 STHdhQ7（野生型）和 STHdhQ111（HD 模型）模型细胞系中进行。用依托泊苷（Eto）处理诱导双链断裂（DSBs），以评估 DNA 损伤反应（DDR）和突触可塑性基因的表达。Eto 处理诱导两种细胞系中 ATM（p-ATM）和 H2AX（γH2AX）的磷酸化，这是 DDR 的标志物。有趣的是，在 DNA 损伤后，与 HD 细胞系模型相比，STHdhQ7 细胞中活性调节细胞骨架相关蛋白（Arc）和 BDNF 的表达增加。此外，Eto 诱导 CREB 激活，其共激活因子在分析的细胞类型中有不同的定位。这些结果表明，DSBs 对正常细胞系与 HD 模型中可塑性基因的基因表达模式产生不同的影响。这种效应是由 HD 模型中 CREB 结合蛋白（CBP）和组蛋白乙酰化的定位受损介导的。我们的结果强调了表观遗传学和 DNA 修复对 HD 的作用，因此我们建议未来的研究应该深入探索神经元病变的表观遗传景观，以进一步了解分子机制并确定治疗靶点。
